Fe²⁺/Fe³⁺ Ions Chelated with Ultrasmall Polydopamine Nanoparticles Induce Ferroptosis for Cancer Therapy

Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Besides, advantages of polymeric nanomaterials in improving anticancer efficacy and reducing side effect are widely accepted. In this work, based on the property of polypodamine to chelate metal ions, ultrasmall poly(ethylene glycol)-modified polydopamine nanoparticles, (UPDA-PEG)@Fe^2+/3+ nanoparticles, a novel ferroptosis agent, was rationally designed by chelating iron ions on ultrasmall polydopamine nanoparticles modified by PEG. This treatment led to a bigger specific surface area, which could support more reactive sites to chelate large number of iron ions, which is beneficial for exploring the detailed mechanism of ferroptosis-induced tumor cell death by iron ions. Also, the pH-dependent release of iron ions can reach approximately 70% at pH 5.0, providing the advantage of application in tumor microenvironment. The in vitro tests showed that the as-prepared NPs exhibit an effective anticancer effect on tumor cells including 4T1 and U87MG cells, yet ferric ions show a stronger ability of killing cancer cells than ferrous ions. Differences between ferrous ions and ferric ions in the ferroptosis pathway were monitored by the change of marker, including reactive oxygen species (ROS), glutathione peroxidase 4, and lipid peroxide (LPO), as well as the promoter and inhibitor of ferroptosis pathway. UPDA-PEG@Fe²⁺ nanoparticles induce ferroptosis that depends more on ROS; however, a more LPO-dependent ferroptosis is induced by UPDA-PEG@Fe³⁺ nanoparticles. Additionally, the in vivo studies using tumor-bearing Balb/c mice demonstrated that the as-prepared NPs could significantly inhibit tumor progression. UPDA-PEG@Fe^2+/3+ nanoparticles reported herein represent the nanoparticles related to iron ions for chemotherapy against cancer through the ferroptosis pathway.